tbuckley/cabot-search huggingface dataset:
<i>WDR49</i> mutation as a novel predictive biomarker in patients with non–small cell lung cancer with immune checkpoint inhibitors.
Authors: Zhihui Shi, Yaqin Liu, Lele Zhao, Lin Chen, Qidong Yang, Mingzhe Xiao
Journal: Journal of Clinical Oncology (2022)

2615 Background: Application of Immune Checkpoint Inhibitors (ICIs) has become the first-line therapy for advanced or metastatic non-small cell lung cancer (NSCLC). WDR49 gene belongs to the WDR (WD40-repeat) protein family which participates in a wide range of biological processes, including DNA damage repair and immune regulation, etc. However, the correlation between WDR49 mutation and immune efficacy is unclear. Methods: A total of three independent cohorts of NSCLC patients treated with immunotherapy were analyzed in this study: the Miao cohort (n = 56), the Rizvi cohort (n = 34), the Hellmann cohort (n = 75). Survival was estimated by Kaplan-Meier curves, with the p value determined by a log-rank test. HR was determined through the univariable and multivariable Cox regression. The CIBERSORT analysis relied on RNA-seq data in The Cancer Genome Atlas (TCGA) database. Two-sided P value &lt; 0.05 was considered statistically significant. All the statistical analyses were conducted with R version 4.0.3. Results: In this merged cohort, the frequency of WDR49 mutation ( WDR49-mut) was 10.30% (17 in 165), and most patients with WDR49 mutation were lung adenocarcinoma (LUAD) (11.85%, 16 in 135). Meanwhile, the frequency of WDR49-mut in TCGA database was 7.05 % and 3.84% in LUAD and lung squamous cell carcinoma (LUSC), respectively. The Kaplan-Meier curves survival analysis indicated that WDR49-mut was associated with longer progression free survival (PFS) (median PFS 23 months vs 5.2 months, hazard ratio [HR] = 0.17 [95% CI, 0.06–0.47], P &lt; 0.001) and higher objective response rate (ORR) (76% vs 27%, P &lt; 0.001). Furtherly, WDR49-mut was significantly related to higher tumor mutational burden (TMB) (median TMB 495 vs 149, P &lt; 0.001), but it had nothing to do with the expression of PD-L1 (Proportion of PD-L1 positive 72.7% vs 68.5%, P = 1). The CIBERSORT analysis revealed that CD8+ T cell infiltration was significantly higher in WDR49-mut group than WDR49 wildtype group (p &lt; 0.05). Conclusions: Better treatment response and survival benefit in the mutant group suggest that the WDR49 mutation may serve as a novel predictive biomarker in NSCLC patients with ICIs. The significantly higher TMB and CD8+ T cell infiltration in WDR49-mut group may be the potential mechanism.
Iron surveillance and management in gastrointestinal oncology patients: A national survey of physician practice.
Authors: Christine Brezden, Alliya Remtulla Tharani, Adriyan Hrycyshyn, Alexandria Abbruzzino, Janet Smith, Jacob Kachura, Michelle Sholzberg, Jeff Mosko, Sami A. Chadi, Ronald L. Burkes
Journal: Journal of Clinical Oncology (2022)

e13644 Background: In 2018, there were an estimated 4.8 million new cases of gastrointestinal (GI) cancers worldwide and 3.4 million related deaths. Iron deficiency (ID) is a frequent complication of GI malignancy that eventually manifests as iron deficiency anemia (IDA). Early recognition and treatment of ID/IDA in GI oncology patients is an important aspect of care. Traditional serum ferritin monitoring and oral iron supplementation hold limited diagnostic and therapeutic value in this population as it may be falsely elevated and confounded by poor absorption and blood loss, respectively. Therefore, we conducted a survey of Canadian physicians to assess disparities in IDA surveillance and management practices in GI cancer patients. Methods: From February 2020 to September 2021, a 20-question electronic survey was sent to Canadian medical oncologists (MO), surgical oncologists (SO), and gastroenterologists (GE). The survey collected information on four domains: demographics, screening practices, treatment practices, and knowledge of the latest guidelines of ID/IDA. Analysis was conducted using descriptive statistics. Results: A total of 108 (55 GE, 19 SO, and 34 MO) of the 872 (12.4%) invited physicians completed the survey. A greater proportion of GE (70.9% compared to 36.8% of SO, and 26.5% of MO) measured baseline iron parameters. Of these, a slight trend of iron parameters were being measured mainly at initial consult (61.5% of GE, 85.7% of SO, and 44.4% of MO), with little continuing surveillance throughout treatment course. Most physicians who measured iron parameters relied on ferritin mainly (82.1% of GE, 100% of SO), while MO were evenly distributed in their evaluation of ferritin (88.9%), serum iron (100%), total iron binding capacity (100%) and iron saturation (88.9%). The majority supplemented iron if ID/IDA was identified prior to systemic/surgical oncologic treatment (94.2% of GE, 85.7% SO, and 66.7% of MO). Of these, parenteral iron was the preferred modality for SO (85.7%), while oral iron was preferred among GE (82.8%) and MO (55.6%). The majority of physicians (81.3%) were not aware of the ASH/ASCO guidelines regarding the use of erythropoiesis stimulating agents in conjunction with parenteral iron supplementation for treatment anemia in this setting (92% of GE, 66.7% of SO, and 80.9% of MO). Conclusions: Results from this Canadian survey suggests a disparity in practice pattern for IDA management between different specialties caring for GI oncology patients. Moreover, there appears to be a gap in knowledge and thus a gap in care surrounding evidence-based IDA management principles which may be contributing to poor clinical outcomes. Focused knowledge translation and exchange efforts are required to improve treatment of ID/IDA in patients with GI cancer nationally.
First-line (L1) therapy targeting EGFR in lung metastases (mets) of colorectal cancer (mCRC): An ARCAD pooled analysis.
Authors: Einat Shacham Shmueli, Morteza Raeisi, Benoist Chibaudel, Timothy S. Maughan, Jean-Yves Douillard, Eric Van Cutsem, Carsten Bokemeyer, Axel Grothey, Richard Adams, John Raymond Zalcberg, Takayuki Yoshino, Jean-Baptiste Bachet, Romain Cohen, Lama Sharara, Thierry Andre, Qian Shi, Aimery De Gramont
Journal: Journal of Clinical Oncology (2022)

3578 Background: Monoclonal antibodies (mab) targeting EGFR are recommended in L1 treatment (trt) for mCRC in patients (pts) with RAS wild-type (WT) tumor and primary left CRC. ARCAD database contains individual data of randomized trials that evaluated anti-EGFR mab plus chemotherapy (CT). In this analysis we aimed to evaluate anti-EGFR benefit in mCRC with lung mets, either as single site or multiple sites. Methods: Individual pts data from four trials (PRIME, CRYSTAL, COIN, OPUS) comparing CT +/- anti-EGFR were pooled. KRAS status was not required at inclusion to these studies. The primary endpoint, overall survival (OS), was estimated using Kaplan-Meier method, prognostic value of lung mets was evaluated by stratified Cox models in pts groups defined by KRAS status. The predictive value was evaluated by interaction test (Int) between trt and lung mets status in pts group defined by KRAS status and considered as significant with a P &lt; 0.1. Results: 3681 pts with known KRAS status were included, 2171 WT and 1510 mutant (MT). Pts characteristics were well balanced. Significant median OS benefit of anti-EGFR was observed in the whole KRAS WT population and in the left colon and rectum subgroup but not in the right colon subgroup. In pts with KRAS WT single site mets, a non-significant benefit of anti-EGFR was observed only among pts without lung mets (N = 642). In pts with lung single site mets (N = 129), a significant benefit ( P= 0.018) in the KRAS MT population (N = 55) was observed, but Int was non-significant ( P =0.157). In pts with KRAS WT and multiple without lung mets sites (N = 673), no benefit of anti-EGFR was observed and Int was significant ( P= 0.054). Pts with KRAS MT multiple sites with (N = 656) or without (N = 397) lung mets, had no benefit of anti-EGFR. The same findings were found in the left primary pts and in the two fluoropyrimidine backbone. PFS analyses confirm the OS results. Conclusions: In this ARCAD analysis pts with lung mets as a single site appear to benefit from anti-EGFR L1 therapy in case of KRAS MT. This unexpected result based on a limited sample size cannot be explained on the knowledge of anti-EGFR therapy. Furthermore, pts with multiple mets sites have a benefit of anti-EGFR therapy only in the presence of lung mets even in KRAS WT left primary tumor. These findings need further confirmation and may initiate the search for a specific molecular phenotype associated with lung mets in CRC pts. [Table: see text]
Oxaliplatin and capecitabine (XELOX) plus toripalimab as perioperative treatment for locally advanced gastric or gastro-esophageal junction adenocarcinoma (Neo-Capture): A single-arm, phase 2 study.
Authors: Zhichao Jiang, Yibin Xie, Bingzhi Wang, Yongjian Zhu, Yan Ke, Wen Zhang, Yongkun Sun, Yin Li, Chengfeng Wang, Dongbing Zhao, Yantao Tian, Ai-Ping Zhou
Journal: Journal of Clinical Oncology (2022)

e16001 Background: PD-1 inhibitor combined with chemotherapy showed remarkable objective response rate in the first line treatment of metastatic gastric cancer. While, the benefit of perioperative PD-1 inhibitor plus chemotherapy in locally advanced gastric or gastro-esophageal junction (G/GEJ) cancer was not clear. Therefore, we aimed to assess the efficacy and safety of perioperative XELOX plus toripalimab in the patients with locally advanced G/GEJ cancer in this study. Methods: This was a prospective single arm phase 2 study. Eligible patients were with histologically confirmed locally advanced G/GEJ (Siewert II/II type) adenocarcinoma (cT3-4 Nany M0 or T1-2 N2-3 M0). Patients received 4 preoperative and 2 postoperative cycles of XELOX plus toripalimab (oxaliplatin 130mg/m 2 D1, capecitabine 1000mg/m 2 bid D1-14, toripalimab 240mg D1, Q3W) followed by subsequent 2 cycles of toripalimab monotherapy. Patients underwent D2 gastrectomy after preoperative treatment. The primary endpoint was major pathological response (MPR) according to Becker TRG criteria. Secondary endpoints included safety, R0 resection rate, pathological complete response (pCR), 3-year disease free survival (DFS) and 3-year overall survival (OS). Results: From Jul, 2019, to Dec, 2021, 35 pts were recruited. The median age was 61 (34-72) years old. 80% of the pts were men. Acutally, all the pts had cT4 (cT4a [48.6%] &amp; cT4b [51.4%]) and 88.6% had cN+ by CT, MRI and ultrasound gastroscopy. 2 pts suffered disease progression during neoadjuvant treatment. 4 pts have not yet completed preoperative therapy. 29 pts had received gastrectomy and 2 pts were pathologically diagnosed with large cell neuroendocrine carcinoma. Therefore, 27 adenocarcinoma pts were included in this analysis. 3 (11.1%) pts achieved pCR (TRG1a) and 4 (14.8%) pts achieved MPR (TRG1a/b). R0 resection was achieved in 96.3% (26/27) of the pts. No patient had pT4b. The most common (≥10%) grade 1-2 treatment related adverse events (TRAEs) included leucopenia (45.7%), neutropenia (42.9%), thrombocytopenia (20%), nausea (34.1%), vomiting (14.3%), anorexia (14.3%), ALT increased (40%) and AST increased (34.3%). Only 4 (11.4%) pts experienced grade 3 neutropenia. No other ≥ grade 3 TRAEs occurred. Most of the potential immune-related adverse events were grade 1-2 including hypothyroidism (8.6%), adrenal insufficiency (2.9%) and hyperglycemia (11.4%). Only one (2.9%) patient had grade 3 hyperglycemia. No serious perioperative complication and death occurred. Conclusions: Perioperative XELOX plus toripalimab preliminarily showed a favorable R0 resection rate and acceptable MPR in cT4a/T4b locally advanced G/GEJ cancer patients with a manageable safety profile. Clinical trial information: NCT04119622.
Five-year results of a phase 2 trial using ipilimumab (I), nivolumab (N), and trabectedin (T) for previously untreated advanced soft tissue sarcoma (NCT03138161).
Authors: Erlinda Maria Gordon, Sant P. Chawla, Victoria S. Chua-Alcala, Ted T. Kim, Noufil Adnan, Simranjit Sekhon, Nicole Angel, Mitchel Fernando, Don Arlen Brigham, Doris V. Quon, Ania Moradkhani, Steve Wong
Journal: Journal of Clinical Oncology (2022)

11573 Background: Understanding the bifunctional role that the immune system plays in tumor eradication vs growth promotion is critical in the design and timing of tumoricidal and immunologic therapies for sarcomas. Hypothesis: Immune checkpoint inhibitors that promote sustained T cell activation would be most effective when given as first line therapy, together with a tumoricidal agent. Methods: Eligible patients for this Phase 2 study are males or females ≥ 18 years of age with locally advanced unresectable or metastatic soft tissue sarcoma, previously untreated, with measurable disease by RECIST v1.1. Treatment protocol: (I) mg/kg i.v. q 12 wks, (N) 3 mg/kg i.v. q 2 wks, (T) 1.2 mg/m2 CIV q 3 wks. Treatment Outcome Parameters: (1) Best objective response rate by RECIST v1.1, (2) Progression-free survival (PFS), (3) Overall survival (OS), and (4) Incidence of treatment-related adverse events. Results: Ninety-nine patients were enrolled. Efficacy analysis (n = 88): There were 8CR (1 surgical CR), 11PR, 58SD, 11PD. Overall response rate was 21.6%, Disease Control Rate, 87.5%. The median PFS was 7 (range:1-44) months, median OS, 14 (range: 1-46) months. Grade 3 TRAEs include fatigue (n = 8), adrenal insufficiency (n = 1), dehydration (n = 1), hyponatremia (n = 2), increased AST (n = 8), increased ALT (n = 24), increased ALP (n = 2), port site infection (n = 2), psoriasis exacerbation (n = 1), anemia (n = 9), thrombocytopenia (n = 2), and neutropenia (n = 5). Grade 4 TRAES include anemia (n = 1), neutropenia (n = 1), thrombocytopenia (n = 2), increased AST (n = 2), increased ALT (n = 2), and increased CPK (n = 2). Grade 5 TRAES include rhabdomyolysis (n = 1). There was no incidence of alopecia nor cardiac toxicity reported. Conclusions: Taken together, these data indicate that first-line combinatorial therapy with Ipilimumab, Nivolumab, and Trabectedin (1) may be more effective than standard first line therapy (doxorubicin/ifosfamide/mesna), and (2) is safer than standard first line therapy for advanced soft tissue sarcoma. Clinical trial information: NCT03138161.
Colorectal cancer mortality rates and socioeconomic factors in Brazil: Association with income inequality and availability of medical doctors.
Authors: Jean Henri Maselli-Schoueri, Luis Eduardo Werneck De Carvalho, Laercio da Silva Paiva, Manuela de Almeida Roediger, Luiz Carlos de Abreu, Fernando Luiz Affonso Fonseca, Fernando Adami
Journal: Journal of Clinical Oncology (2022)

e22516 Background: Colorectal cancer mortality is expected to rise in the upcoming years in Brazil, especially in less developed regions. It is also known that socioeconomic factors play a role not only in the development, but also in the outcome of this disease. Methods: Ecological study that analyzed secondary data from 2016-2018 to examine the relationship between both income-inequality and the amount of doctors per inhabitant on colorectal cancer mortality in Brazil and its Federative Units. All data were gathered from Brazil’s public health system. Mortality was standardized by the World Health Organization’s population and analyzed by sex and age. Income-Inequality was measured using the Gini index, obtained from the United Nations Development Programme. The number of doctors was obtained from the Unified Health System and also calculated as the rate per 100,000 inhabitants. For this study, linear regression was performed using stepwise selection/backward elimination. Results: In the present study, we found that female sex (β -0.616, IC95% -1.308;0.075), the number of gastroenterologists (β -2.506, IC95% -3.702;-1.309), clinicians (β -0.107, IC95% -0.155; -0.0600), and the number of general surgeons (β -0.845, IC95% -1.188; -0.501) were negatively associated with colorectal cancer mortality, whereas higher income (β 0.02, IC95% 0.001;0.003), the amount of doctors in the public health system as a whole (β 0.090, IC95% 0.064;0.116), generalists (β 1.760, IC95% 0.987; 2.533) and oncology surgeons (β 14.252, IC95% 3.937; 24.566), were positively associated with cancer mortality. Conclusions: Colorectal cancer presents different mortality rates depending on sex, socioeconomic status and availability of medical doctors and specialists, whether for diagnosis and higher notifications or treatment and lesser deaths form the disease.
Activity of tivozanib in non-clear cell renal cell carcinoma (nccRCC): Subgroup analysis from a phase 2 randomized discontinuation trial.
Authors: Pedro C. Barata, Kim Allman, Aviva G. Asnis-Alibozek, Vijay Kasturi, Sumanta K. Pal
Journal: Journal of Clinical Oncology (2022)

4542 Background: Non-clear cell renal cell carcinoma (nccRCC) is a blanket term for a collection of heterogenous and biologically diverse RCC histologies including (but not limited to) papillary, chromophobe and unclassified subtypes. Tivozanib is a selective VEGFR tyrosine kinase inhibitor with demonstrated activity in RCC with clear cell component. Here we report efficacy of tivozanib in a histologically diverse nccRCC subset included in a phase 2 study. Methods: We conducted a subgroup analysis of patients with nccRCC enrolled in the study 201 (NCT00502307), a phase 2 randomized discontinuation trial of tivozanib in patients with RCC who had no prior VEGF targeted treatment. Clinical outcomes including overall response rate (ORR), disease control rate (DCR, defined by CR+PR+SD), and progression free survival (PFS) were examined. Safety outcomes for all patients are reported in the original publication (Nosov, JCO 2012). Results: Of the 272 patients enrolled, 46 (16.9%) patients had nccRCC. [11 (4%) papillary, 2 (0.7%) chromophobe, 2 (0.7%) collecting duct, and 31 (11.4%) unclassified/mixed]. Of the 46 nccRCC patients, the ORR was 17.4% by investigator (INV) review and 15.2% by independent radiology review (IRR). The DCR was 80.4% by INV and IRR. The median PFS was 6.7 months (204 days) (95%CI: 125-366 days) by IRR (Figure 1). Of note, 14 patients with SD after 16 weeks on tivozanib were randomized to 12 weeks of placebo and may have progressed during that timeframe before unblinding and resuming tivozanib. Safety was not analyzed by histology but there were no new safety signals and was consistent with tivozanib labelling in the ITT population. Conclusions: Tivozanib demonstrated activity and a favorable safety profile in patients with nccRCC. This data adds to the body of evidence supporting VEGFR TKI use in advanced RCC including in non-clear cell histologies. Clinical trial information: NCT00502307. [Table: see text]
Phase 3, multicenter, randomized study of CPI-613 with modified FOLFIRINOX (mFFX) versus FOLFIRINOX (FFX) as first-line therapy for patients with metastatic adenocarcinoma of the pancreas (AVENGER500).
Authors: Philip Agop Philip, Nathan Bahary, Amit Mahipal, Anup Kasi, Caio Max Sao Pedro Rocha Lima, Angela Tatiana Alistar, Paul Eliezer Oberstein, Talia Golan, Vaibhav Sahai, Jean Philippe Metges, Jill Lacy, Christos Fountzilas, Charles D. Lopez, Michel Ducreux, Pascal Hammel, Mohamed E. Salem, David Lawrence Bajor, Al Bowen Benson, Marc E. Buyse, Eric Van Cutsem
Journal: Journal of Clinical Oncology (2022)

4023 Background: Metastatic pancreatic cancer (mPC) remains a deadly disease with very limited treatment options. FFX is a standard first-line therapy for mPC with a median overall survival (mOS) of 11.1 months. CPI-613 is a stable intermediate of a lipoate analog that inhibits pyruvate dehydrogenase and α-ketoglutarate dehydrogenase enzymes of the tricarboxylic cycle preferentially within the mitochondria of cancer cells. In a phase I study, CPI-613+mFFX was safe and exhibited promising signal of efficacy. Methods: A global, randomized phase 3 trial was conducted across 73 sites to investigate the efficacy and safety of CPI-613 in combination with mFFX compared to standard dose FFX in treatment-naïve patients with mPC. Treatment was administered in 2-weekly cycles until progression or intolerable toxicity. In the experimental arm, CPI-613 at 500 mg/m 2 was given intravenously on days 1 and 3. The doses of irinotecan, oxaliplatin, and 5-fluorouracil in the experimental arm were 65 mg/m 2 , 140 mg/m 2 , and 2,400 mg/ 2 , respectively. Primary endpoint was OS. Secondary endpoints were progression-free survival (PFS), overall response rate (ORR), duration of response, pharmacokinetics, patient reported outcomes and safety. Results: 528 patients were randomly assigned (266 in test and 262 in control arm). There were 362 deaths, with a mOS of 11.1 months for CPI-613+mFFX vs. 11.7 months for FFX [hazard ratio (HR), 0.95; 95% CI, 0.77 to 1.18; P = 0.655]; mPFS was 7.8 months vs. 8.0 months respectively [HR, 0.99; 95% CI, 0.76 to 1.29; P = 0.94]; ORR was 39% in the test arm vs. 34% in the control arm [ORR ratio, 1.23 (95% CI, 0.86 to 1.75)]. Grade ≥ 3 treatment-emergent adverse events with ≥ 10% frequency in CPI-613 plus mFFX vs. FFX arm were diarrhea (11.2% vs. 19.6%), hypokalemia (13.1% vs. 14.9%), anemia (13.9% vs. 13.6%), neutropenia (11.2% vs. 14.0%), thrombocytopenia (11.6% vs. 13.6%) and fatigue (10.8% vs. 11.5%). Conclusions: The addition of CPI-613 to mFFX failed to show significant improvements of ORR, PFS or OS. The mFFX in the test arm that had the lowest prospectively tested doses of FFX was without compromise on PFS or OS and may be considered as a reference for future FFX administration. Clinical trial information: NCT03504423.
Lymph node dissections and survival in sublobar resection of non-small cell lung cancer ≤ 20 mm.
Authors: Shinkichi Takamori, Takefumi Komiya, Emily Powell
Journal: Journal of Clinical Oncology (2022)

e20583 Background: A recent Japanese phase III randomized trial of lobectomy versus segmentectomy for small-sized (≤ 20 mm) peripheral non-small cell lung cancer (NSCLC) (JCOG 0802) showed that patients who had undergone segmentectomy had a significantly longer overall survival (OS) in comparison with those who had lobectomy. More attention is needed regarding the required extent of thoracic lymphadenectomy in patients with small-sized NSCLC who undergo sublobar resection. Methods: The National Cancer Database was queried for patients with clinically node-negative NSCLC ≤ 20 mm who had undergone sublobar resection between 2004 and 2017. OS of NSCLC patients by the number of lymph node dissections (LNDs) was analyzed using Log-rank tests and Cox proportional hazards model. The cut-off value of the LNDs was set to 10 according to the Commission on Cancer’s recommendation. Results: This study included 4,379 segmentectomy and 23,138 wedge resection cases. The sequential improvement in the HRs by the number of LNDs was evident, and the HR was the lowest if the number of LNDs exceeded 10. Patients with ≤ 9 LNDs had a significantly shorter OS than those with ≥ 10 LNDs (hazard ratio [HR]: 1.50, 95% confidence interval [CI]: 1.40–1.61, P &lt; 0.0001). Multivariable analysis revealed that performing ≤ 9 LNDs was an independent factor for predicting OS (HR for death: 1.34, 95% CI: 1.24–1.44, P &lt; 0.0001). These results remained significant in subgroup analyses by the type of sublobar resection (segmentectomy, wedge resection). Conclusions: Performing ≥ 10 LNDs has a prognostic role in patients with small-sized NSCLC even if the resection is sublobar.